Problems with balance are a leading cause of death and injury in elderly populations. Despite the prevalence of this problem little is known about the molecular mechanisms regulating development and pathology of the vestibular system. This is in part due to the very limited availability of tissue. Well characterized mouse mutants and techniques for separating and sequencing small amounts of protein provide a means to identify and clone genes that are expressed in the vestibular system. This in turn will allow a biochemical and genetic analysis of this sensory system and eventually an understanding of molecular mechanisms underlying pathologic changes that affect the vestibular system. We have begun to characterize a mouse mutant (tilted) with a very specific vestibular defect; the absence of otoconia. We hypothesize that the mutation in the tilted mouse results in a missing or defective protein that is involved in the formation or structure of otoconia. Additional otoconial proteins may also be missing secondary to the tilted mutation. The tilted mouse is unique with respect to other vestibular mouse mutants in that the phenotype is restricted to the vestibular system and has a penetrance of 100 percent. We propose to use this mouse mutant to identify and partially sequence proteins specifically expressed in the vestibular system and to clone cDNAs/genes coding for these proteins. This work will allow us to express and characterize these vestibular proteins in vitro, to develop antibodies and to target the expression of foreign genes to the vestibular system in vivo using transgenic mice. Furthermore, human homologues of these mouse proteins can be cloned allowing a direct molecular assessment of vestibular pathology in the human population. Human otoconia are subject to aging, drug and disease related pathology. In combination with age-related degeneration of sensory cells, these dysfunctions contribute significantly to the susceptibility of aged individuals to falling. In postmenopausal women this danger is compounded by osteoporosis, with the sequela of bone fracture. In 1991 it was estimated that the medical care for treating individuals with balance related disorders cost $1 billion per year.